Hydrolysis of Iminium Ethers Derived from the Reaction of Ketones with Hydroxy Azides:  Synthesis of Macrocyclic Lactams and Lactones

Forsee, Jennifer E.; Aubé, Jeffrey

doi:10.1021/jo990041h

Cited by 43 publications

(24 citation statements)

References 9 publications

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“…In another such process, nitrogen insertion/ring expansion of cyclic ketones provided either macrolactams (209) or macrolactones (210), with the relative proportions dependent on the ring size of the precursor and the pH of the reaction medium (Figure 11.16, reagents common for both products indicated). 319 The relative simplicity of these structures speaks clearly to the limitations of such approaches.…”

Section: Ring Expansion/openingmentioning

confidence: 99%

The Synthesis of Macrocycles for Drug Discovery

Peterson¹

2014

Macrocycles in Drug Discovery

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Despite the attractive nature of macrocyclic compounds for use in new pharmaceutical discovery, applications have been hindered due to the lack of appropriate synthetic methods, in particular for the construction of libraries of such molecules. However, over the last decade, a number of effective and versatile methodologies suitable for macrocyclic scaffolds have been developed and applied successfully. These include classical coupling and substitution reactions, ring-closing metathesis (RCM), cycloaddition (“click”) chemistry, multicomponent reactions (MCR), numerous organometallic-mediated processes and others. This chapter presents a comprehensive compilation of these strategies and provides examples of their use in drug discovery, along with a description of those approaches that have proven effective for the assembly of macrocyclic libraries suitable for screening.

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Section: Ring Expansion/openingmentioning

confidence: 99%

The Synthesis of Macrocycles for Drug Discovery

Peterson¹

2014

Macrocycles in Drug Discovery

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“…26,27 In some cases, a modest level of product control is possible by variation of reaction conditions. For example, when a strong base such as KOH (pH ca.…”

Section: Reactions Of Hydroxyalkyl Azidesmentioning

confidence: 99%

Schmidt Rearrangement Reactions with Alkyl Azides

Grecian¹,

Aubé

2009

Organic Azides

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The sobriquet ' Schmidt reaction ' refers to a number of related processes in which hydrazoic acid or an alkyl azide reacts with an electrophile. 1 -6 The product obtained will depend on the reaction partner (carboxylic acids generate amines, aldehydes give nitriles and formamides, and ketones provide amides, respectively) but all of these reactions have certain features in common. They are the initial nucleophilic addition of the azide component to an electrophile (usually promoted by acid) eventually followed by a rearrangement step driven by the energetically favorable loss of nitrogen. The classical Schmidt reaction of hydrazoic acid with ketones is generally considered to involve an intermediate dehydration step. 7,8 Despite the diversity of reactions that comprise the Schmidt family, its single most common variant is shown in Scheme 7.1 . This overall process can be regarded as an insertion of NH between the carbonyl and an α alkyl group. 9 The development of this version of the Schmidt reaction predates the experience of anyone working in organic chemistry today (Schmidt ' s original report was in 1924) but the extension of the concept to nucleophilic alkyl azides is a decidedly contemporary development. For example, if one compares the two reactions shown in Scheme 7.2 , it is clear that the direct insertion of an alkyl azide into cyclohexanone allows for the introduction of additional nitrogen atom substitution and, in the case of an alkyl azide tethered to a carbonyl substrate, the possibility of an intramolecular reaction. The goal of this chapter

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“…In principle, they react with electron-deficient compounds at N 1 [20][21][22][23][24] and electron-rich compounds at N 3 [25][26][27][28]. There can be not only retention of the azide unit but also cleavage of the nitrogenAnitrogen single bond, as in the case of nitrene chemistry [29][30][31][32].…”

Section: Introductionmentioning

confidence: 99%

A selective synthesis of enamines versus aziridines

Belei

Bîcu

Jones

et al. 2010

Journal of Heterocyclic Chem

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The reaction of 10‐azidoacetyl‐10H‐phenothiazine with olefinic dipolarophiles depends on the reaction temperature. In refluxing toluene, a mixture of enamine and aziridine is formed in 3:1 ratio. The reaction mechanism appears to involve a Michael‐type addition of the nucleophilic N1 azide atom to the olefinic double bond. In chloroform, a cycloaddition reaction takes place with the formation of a 4,5‐dihydro‐1,2,3‐triazole. The heating of dihydrotriazoles in toluene is accompanied by nitrogen elimination leading to a mixture of enamine and aziridine in 1:3 ratio. J. Heterocyclic Chem., 2011.

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Hydrolysis of Iminium Ethers Derived from the Reaction of Ketones with Hydroxy Azides: Synthesis of Macrocyclic Lactams and Lactones

Cited by 43 publications

References 9 publications

The Synthesis of Macrocycles for Drug Discovery

The Synthesis of Macrocycles for Drug Discovery

Schmidt Rearrangement Reactions with Alkyl Azides

A selective synthesis of enamines versus aziridines

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